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In past researches, we had been proved the action mechanism of pre-germinated brown rice (PGBR) to treat metabolic syndrome and diabetes mellitus. This study was to investigate the protective effect of PGBR in high fructose and high fat-induced non-alcoholic fatty liver disease (NAFLD) in rodents. WKY rats were divided into: Control group was fed normal drinking water and diet; FLD group was fed 10% high-fructose-water (HFW) and high-fat-diet (HFD); PGBR group was given HFW, and HFD mixed PGBR. After four weeks, the body, hepatic and cardiac weight gains of FLD group had significant increases than that of Control group. The enhanced blood pressure and heart rate, hypertriglyceridemia, hyperuricemia, and higher liver function index (GPT levels) were observed; meanwhile, the IL-6 and TNF-α levels of serum, and TG level of liver were also elevated in FLD group. The related protein expressions of lipid synthesis, inflammation, cardiac fibrosis, and hypertrophy were deteriorated by HFW/HFD. However, in treatment group, PGBR decreased all above influenced parameters, additionally GOT; and related protein expressions. PGBR treated HFW/HFD-induced NAFLD and cardiac complications might be via improving lipid homeostasis, and inhibiting inflammation. Together, PGBR could be used as a healthy food for controlling NAFLD and its' cardiac dysfunction.

In this study we aimed at demonstrating the ability of Magnolia officinalis water extract to ameliorate gastric ulcers in in vitro and in vivo experiments. The gastric mucosa epithelial cell line, RGM 1, was pretreated with Magnolia officinalis water extract (0, 0.1, 1, 2, 5, or 10 mg/ml) and cultured in DMEM/F12 medium (pH 7.4) for 2 h and then in DMEM/F12 medium (pH 4.0) for 10 min. Magnolia officinalis water extract protected the cell viability and decreased reactive oxygen species formation by the acidic medium. In the in vivo experiment, Magnolia officinalis water extract (100 mg/kg) was administrated daily for 28 days in ICR mice via oral gavage, and then Shay’s ulcer surgical method was performed to induce gastric ulcers. We analyzed the pH value of stomach acid and the pathological section, inflammation, and cannabinoid receptor type 2 (CB2) cDNA levels of the stomach. Magnolia officinalis water extract not only enhanced the pH value of stomach acid but also ameliorated the ulcer index and inflammation and increased CB2 expression effectively. These results suggest that Magnolia officinalis water extract might be used to decrease the incidence of gastric ulcer.

This study was to investigate three agents possible protective effect against DM-induced cardiovascular dysfunction in spontaneously hypertensive rats (SHR). Control group was fed normal diet, DM group was injected with STZ/NA and fed high fat diet (HFD), and treatment groups were given STZ/NA, fed HFD, and then oral gavaged with eugenosedin-A (Eu-A), glibenclamide (Gli), or pioglitazone (Pio) 5 mg/kg/per day for 4-week, respectively. Eu-A, Gli, and Pio clearly ameliorated the changes of body weight, cardiac weight, and the biochemical parameters, cardiovascular disorders and inflammation. Like Gli and Pio, Eu-A may be effectively to control DM and the cardiovascular dysfunction.

Objectives Eugenosedin-A (Eu-A), an adrenergic and serotonergic antagonist, is known to have anti-metabolic syndrome effects. In this study, we evaluated its protective effects against diabetes mellitus (DM) in spontaneous hypertensive rats (SHR) and compared it with two anti-diabetes medications, glibenclamide (Gli) and pioglitazone (Pio). Methods We divided 10-week-old SHRs into five groups: a control group fed a normal diet; an untreated DM group induced by injecting the SHRs with STZ/NA and feeding them a high-fat diet (HFD); and three treated groups (after giving STZ/NA and HFD) gavage given with Eu-A, Gli or Pio (5 mg/kg per day) for 4 weeks. Key findings The untreated DM group weighed less and had hyperglycaemia, hypoinsulinemia and hyperlipidemia. They were also found to have aberrant glucose-dependent insulin pathways, glucose metabolism and lipid synthesis proteins, while the controls did not. Eu-A, Gli and Pio ameliorated the above biochemical parameters in the treatment groups. Eu-A and Pio, but not Gli, improved hypertension and tachycardia. Conclusions Taken together, Eu-A ameliorated DM, hypertension and tachycardia by improving glucose, lipid homeostasis and anti-adrenergic, serotonergic activities. We concluded that Eu-A could be used in the development of an effective agent for controlling DM and its complications.

Eugenosedin-A (Eu-A) has been shown to protect against hyperglycemia- and hyperlipidemia-induced metabolic syndrome. We investigated the relationship of KATP channel activities and insulin secretion by Eu-A in vitro in pancreatic β-cells, and examined the effect of Eu-A on streptozotocin (STZ)/nicotinamide (NA)-induced type 2 diabetes mellitus (T2DM) in vivo. We isolated pancreatic islets from adult male Wistar rats (250–350 g) and identified pancreatic β-cells by the cell size, capacitance and membrane potential. Perforated patch-clamp and inside-out recordings were used to monitor the membrane potential (current-clamp mode) and channel activity (voltage-clamp mode) of β-cells. The membrane potential of β-cells was raised by Eu-A and reversed by the KATP channel activator diazoxide. Eu-A inhibited the KATP channel activity measured at − 60 mV and increased the intracellular calcium concentration ([Ca2+]i), resulting in enhanced insulin secretion. Eu-A also reduced Kir6.2 protein on the cell membrane and scattered in the cytosol under normal glucose conditions (5.6 mM). In our animal study, rats were divided into normal and STZ/NA-induced T2DM groups. Normal rats fed with regular chow were divided into control and control+Eu-A (5 mg/kg/day, i.p.) groups. The STZ/NA-induced diabetic rats fed with a high-fat diet (HFD) were divided into three groups: T2DM, T2DM+Eu-A (5 mg/kg/day, i.p.), and T2DM+glibenclamide (0.5 mg/kg/day, i.p.; a KATP channel inhibitor). Both Eu-A and glibenclamide decreased the rats’ blood glucose, prevented weight gain, and enhanced insulin secretion. We found that Eu-A blocked pancreatic β-cell KATP channels, caused membrane potential depolarization, and stimulated Ca2+ influx, thus increasing insulin secretion. Furthermore, Eu-A decreased blood glucose and increased insulin levels in T2DM rats. These results suggested that Eu-A might have clinical benefits for the control of T2DM and its complications.

Eugenosedin-A (Eu-A) has been shown to protect against hyperglycemia- and hyperlipidemia-induced metabolic syndrome. We investigated the relationship of K

The aim of this study is to discuss the non-catechin flavonoids (NCF) from Camellia sinensis (L.) O. Kuntze seed improving TNF-α impaired insulin stimulated glucose uptake and insulin signaling. Flavonoids had anti-metabolic syndrome and anti-inflammatory properties. It had widely been known for biological activity of catechins in tea, but very few research reports discussed the biological activity of non-catechin flavonoids in tea seed. We used HepG2 cell to treat with 5 μM insulin or with 5 μM insulin + 30 ng/ml TNF-α. Detecting the glucose concentration of medium, insulin decreased the glucose levels of medium meant that insulin promoted glucose uptake into cells, but TNF-α inhibited the glucose uptake effect of insulin. Furthermore, insulin increased the protein expressions of IR, IRS-1, IRS-2, PI3K-α, Akt/PKB, GLUT-2, AMPK, GCK, pyruvate kinase, and PPAR-γ. TNF-α activated p65 and MAPKs (p38, JNK1/2 and ERK1/2), iNOS and COX-2 which worsened the insulin signaling expressions of IR, IRS-1, IRS-2, PI3K-α, Akt/PKB, GLUT-2, AMPK, GCK, pyruvate kinase, and PPAR-γ. We added NCF (500, 1000, 2000 ppm) to cell with insulin and TNF-α. Not only glucose levels of medium were lowered, and the protein expressions of insulin signaling were increased, but p38, JNK1/2, iNOS and COX-2 were also reduced. NCF could ameliorate TNF-α induced insulin resistance through inhibiting p38, JNK1/2, iNOS and COX-2, and suggested that it might be used in the future to help control insulin resistance. This finding is the first report to present the discovery. Keywords: Flavonoids, Camellia sinensis (L.) O. Kuntze seed, TNF-α, Insulin resistance

This research aims to delineate the anti-inflammatory effect of pregerminated brown rice extract (PE) and γ-oryzanol on improving metabolic features of high-fat diet (HFD)-induced metabolic syndrome (MetS) mouse model. C57BL/6 mice were randomly divided into eight groups: regular diet (RD), HFD, HFD-combined treatment of 0.5, 5, or 10 mg kg-1 day-1 oral gavage γ-oryzanol, and 30, 300, or 600 mg kg-1 day-1 PE for 18 weeks. HFD-fed mice showed overweight, hyperglycemia, hyperlipidemia signs of metabolic disorder, and elevation of inflammatory cytokines such as IL-6, TNF-α, IFN-γ, NO, PGE2 in serum and MAPKs, transcription factor p65, iNOS, and MDA in the liver. In contrast, HFD-fed mice showed lower levels of adiponectin in serum and antiperoxidation enzymes GPx, SOD, and catalase in the liver. While HFD-fed mice cotreated with PE or γ-oryzanol, HFD-induced metabolic disorders, ROS, and inflammation were improved. The anti-MetS, antioxidative stress and anti-inflammation properties of PE were more potent than γ-oryzanol. PRACTICAL APPLICATIONS: Our study showed that PE or γ-oryzanol supplement could help control metabolic disorders, oxidative stress, chronic inflammation, and related complications.

This study examined the effects of eugenosedin-A (Eu-A) in a streptozotocin (STZ)/nicotinamide-induced rat model of type II diabetes mellitus (T2DM). Six-week-old Sprague–Dawley rats were randomly divided into three groups: (1) RD group, normal rats fed a regular diet (RD), (2) DM group, T2DM rats fed a high-fat diet, and (3) Eu-A group, T2DM rats fed a high fat diet plus oral Eu-A (5 mg/kg/day). After 30 days, the DM group had higher body weight, higher blood glucose and lower insulin levels than the RD group. The DM group also had increased protein expression of glycogen synthase kinase (GSK) in liver and skeletal muscle and decreased protein expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), IRS-2, AMP-activated protein kinase (AMPK), glucose transporter-4 (GLUT-4), glucokinase (GCK), and peroxisome proliferator-activated receptor γ (PPAR-γ). STZ/nicotinamide-induced T2DM increased the expression of mitogen-activated protein kinases (MAPKs: p38, ERK, JNK) and inflammatory p65 protein. In the Eu-A treated T2DM rats, however, blood glucose was attenuated and the insulin concentration stimulated. Changes in IR, IRS-1 and IRS-2 proteins as well as AMPK, GLUT-4, GCK, GSK, PPAR-γ, MAPKs, and inflammatory p65 proteins were ameliorated. These results suggested that Eu-A alleviates STZ/nicotinamide-induced hyperglycemia by improving insulin levels and glucose metabolism, and inhibiting the MAPKs- and p65-mediated inflammatory pathway.

To investigate using pre-germinated brown rice (PGBR) to treat metabolic syndrome, we fed one group of mice standard-regular-diet (SRD) for 20 weeks and another group of mice high-fat-diet (HFD) for 16 weeks. We subdivided them into HFD group and HFD + PGBR group whose dietary carbohydrate was replaced with PGBR for 4 weeks. The HFD group gained more weight, had higher blood pressure, heart rate, blood glucose and lipids, liver levels of TG, feces TG and bile acid, lower adipose levels of adipocytokine, lower skeletal muscle IR, IRS-1, IRS-2, PI3 K, Akt/PKB, GLUT-1, GLUT-4, GCK and PPAR-γ; higher liver SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7α1 and PPAR-α, and higher adipose SREBP-1, SCD-1, FAS, and lower adipose PPAR-α and adiponectin. The HFD + PGBR group had clearly improved blood pressure, biochemical parameters and above proteins expressions. PGBR successful treatment of metabolic syndrome was achieved through improvements in glucose and lipid synthesis and metabolism.

The aim of this study is to discuss the non-catechin flavonoids (NCF) from Camellia sinensis (L.) O. Kuntze seed improving TNF-α impaired insulin stimulated glucose uptake and insulin signaling. Flavonoids had anti-metabolic syndrome and anti-inflammatory properties. It had widely been known for biological activity of catechins in tea, but very few research reports discussed the biological activity of non-catechin flavonoids in tea seed. We used HepG2 cell to treat with 5 μM insulin or with 5 μM insulin + 30 ng/ml TNF-α. Detecting the glucose concentration of medium, insulin decreased the glucose levels of medium meant that insulin promoted glucose uptake into cells, but TNF-α inhibited the glucose uptake effect of insulin. Furthermore, insulin increased the protein expressions of IR, IRS-1, IRS-2, PI3K-α, Akt/PKB, GLUT-2, AMPK, GCK, pyruvate kinase, and PPAR-γ. TNF-α activated p65 and MAPKs (p38, JNK1/2 and ERK1/2), iNOS and COX-2 which worsened the insulin signaling expressions of IR, IRS-1, IRS-2, PI3K-α, Akt/PKB, GLUT-2, AMPK, GCK, pyruvate kinase, and PPAR-γ. We added NCF (500, 1000, 2000 ppm) to cell with insulin and TNF-α. Not only glucose levels of medium were lowered, and the protein expressions of insulin signaling were increased, but p38, JNK1/2, iNOS and COX-2 were also reduced. NCF could ameliorate TNF-α induced insulin resistance through inhibiting p38, JNK1/2, iNOS and COX-2, and suggested that it might be used in the future to help control insulin resistance. This finding is the first report to present the discovery.

This study investigated the effect and mechanism of pre-germinated brown rice (PGBR) prevented hyperglycemia in C57BL/6J mice fed high-fat-diet (HFD). Normal six-week-old mice were randomly divided into three groups. Group 1 was fed standard-regular-diet (SRD) and group 2 was fed HFD for 16 weeks. In group 3, the mice were fed a HFD with its carbohydrate replaced with PGBR for 16 weeks. Comparing the SRD and HFD groups, we found the HFD group had higher blood pressure, higher concentrations of blood glucose and HbA1c. The HFD group had less protein expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3K), glucose transporter-4 (GLUT-4) and glucokinase (GCK) and greater expression of glucogen synthase kinase (GSK) in skeletal muscle. The HFD group also had less expression of IR, serine/threonine kinase PI3K-linked protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), GCK and peroxisome proliferator-activated receptor γ (PPARγ) in liver. In the HFD + PGBR group, the PGBR could reverse the disorders of blood pressure, blood glucose, HbA1c and increase insulin concentration. PGBR increased the IR, IRS-1, PI3K, Akt, GLUT-1 and GLUT-4 proteins, and ameliorated AMPK, GCK, GSK and PPARγ proteins. Together, PGBR prevented HFD-induced hyperglycemia through improving insulin levels, insulin receptor, glucose transporters and enhancing glucose metabolism.

Pre-germinated brown rice (PGBR) could ameliorate metabolic syndrome, however, not much research estimates the effect of PGBR extract on insulin resistance. The aim of this study is to examine the effects of PGBR extract in TNF-α induced insulin resistance. HepG2 cells, hepatocytes, were cultured in DMEM medium and added with 5 μM insulin or with insulin and 30 ng/ml TNF-α or with insulin, TNF-α and PGBR extract (50, 100, 300 μg/ml). The glucose levels of the medium were decreased by insulin, demonstrating insulin promoted glucose uptake into cell. However, TNF-α inhibited glucose uptake into cells treated with insulin. Moreover, insulin increased the protein expressions of AMP-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3-kinase-α (PI3K-α), serine/threonine kinase PI3K-linked protein kinase B (Akt/PKB), glucose transporter-2 (GLUT-2), glucokinase (GCK), peroxisome proliferator activated receptor-α (PPAR-α) and PPAR-γ. TNF-α activated p65 and MAPKs (JNK1/2 and ERK1/2) which worsened the expressions of AMPK, IRS-1, PI3K-α, Akt/PKB, GLUT-2, GCK, glycogen synthase kinase-3 (GSK-3), PPAR-α and PPAR-γ. Once this relationship was established, we added PGBR extract to cell with insulin and TNF-α. We found glucose levels of medium were lowered and that the protein expressions of AMPK, IRS-1, PI3K-α, Akt/PKB, GLUT-2, GCK, GSK-3, PPAR-α, PPAR-γ and p65, JNK1/2 were also recovered. In conclusion, this study found that TNF-α inhibited insulin stimulated glucose uptake and aggravated related proteins expressions, suggesting that it might cause insulin resistance. PGBR extract was found to ameliorate this TNF-α induced insulin resistance, suggesting that it might be used in the future to help control insulin resistance.

Eugenosedin-A (Eu-A) effects on vascular endothelial dysfunction and oxidative stress in a hyperlipidemic rat model were investigated. Rats were randomly divided into four groups: two control groups and two treatment groups. The control rats received a regular diet or high fat diet (HFD); the treatment rats fed received an HFD with 5 mg/kg Eu-A or atorvastatin for 10 weeks. No changes in serotonin levels were observed in the four groups; norepinephrine levels were enhanced in the HFD group which was attenuated by Eu-A and atorvastatin. In the HFD group, the vascular reactivity was increased by vasoconstrictors (5-nonyloxytryptamine, 5-HT, and phenylephrine) and decreased by an endothelium-dependent vasorelaxant, carbachol. Protein levels of α1-adrenergic receptors (not 5-HT1B/2A), reactive oxygen species (ROS) p47phox, p67phox, and gp91phox, and oxidative damage markers 3-nitrotyrosine (3-NT) and 4-hydroxy-2-nonenal (4-HNE) were increased, but endothelial nitric oxide synthase (eNOS), P-eNOS and vasodilator-stimulated phosphoprotein phosphorylation (P-VASP) were decreased. Catalase and superoxide dismutase (SOD-1 and SOD-2) proteins were increased, but glutathione peroxidase (GPx) was decreased in the aorta. Eu-A and atorvastatin reduced vasoconstrictor-induced aortic contractions that might be related to 5-HT1B/2A and α1-adrenergic receptors inhibitory activities. Eu-A and atorvastatin improved eNOS/P-eNOS, P-VASP, GPx, and malondialdehyde (MDA) levels, and decreased ROS and oxidative damage markers. Taken together, we suggest that Eu-A can ameliorate hyperlipidemia-induced vascular endothelial dysfunction and oxidative dysregulation.

This study examined the effect of pre-germinated brown rice extract (PGBRE), containing no dietary fibers, but γ-oryzanol, γ-aminobutyric acid (GABA), flavonoids, and anthocyanidin, on high-fat-diet (HFD)-induced metabolic syndrome. C57BL/6 mice were divided into five groups: regular diet, HFD, HFD with oral PGBRE 30, 300, or 600 mg/kg per day for 18 weeks. In the HFD group, higher body and liver weight gain, hyperglycemia, HbA1c, and insulin; higher TG, TC, LDL-C, non-HDL, atherosclerosis index, lower HDL, adiponectin in blood; higher TG in the liver; higher TG, bile acid in feces; and lower protein levels of AMP-activated protein kinase, insulin receptor, insulin receptor substrate-1, insulin receptor substrate-2, peroxisome proliferator-activated receptor-γ, phosphatidylinositol-3-kinase, Akt/PKB, glucose transporter-1, glucose transporter-4, glucokinase in the skeletal muscle; lower glucagon-like peptide 1 (GLP-1) in the intestine; higher sterol regulatory element-binding protein-1 (SREBP-1), stearoyl-CoA desaturase 1 (SCD-1), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9 (PCSK9), and lower PPAR-α, low-density lipoprotein receptor, cholesterol-7α-hydroxylase in the liver; higher SREBP-1, SCD-1, FAS, and lower PPAR-α, adiponectin in the adipose tissue were found. In HFD + PGBRE groups, the above biochemical parameters were improved. PRACTICAL APPLICATIONS: According to the results, we suggested that dietary fibers played a minor role in this study. Extract of PGBR, excluding dietary fiber, showed beneficial activity to ameliorate metabolic syndrome. γ-oryzanol, GABA, flavonoids, and anthocyanidin in PGBRE can inhibit HFD-induced metabolic syndrome and we demonstrated clearly its action mechanisms. This is the first report to examine the relation between PGBRE, GLP-1, and PCSK9. Taken together, PGBRE can potentially be used to develop a good supplement to control metabolic syndrome.

Preclinical Research In this study the effects of low-dose aspirin (5 mg/kg) on adhesion molecule and chemokine expression in a hyperlipidemic rat model. Six-week-old Sprague-Dawley (SD) rats were assigned to two control groups receiving either a regular diet or high-fat diet (HFD) and a treatment group fed HFD with 5 mg/kg aspirin for a 10-week period. Compared with the regular diet control group, the HFD control group had higher body weight, lower levels of high-density lipoprotein, higher concentrations of insulin, triglyceride, total cholesterol, and low-density lipoprotein, but no differences in blood glucose and glycated hemoglobin. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) were clearly shortened in the HFD group. That group also had increased expression of intercellular adhesion molecule-1 (ICAM-1), ICAM-2, ICAM-3, vascular cell adhesion molecule (VCAM), platelet endothelial cell adhesion molecule (PECAM) and P-selectin in platelets and vascular adhesion protein-1 in lymphocyte and in aorta increased expressions of ICAM-1, ICAM-2, ICAM-3, VCAM, PECAM, E-selectin, monocyte chemoattractant protein-1 (MCP-1) and CCR2. The HFD rats also had increased PKCα, IκB kinase α (IKKα), p65, mitogen-activated protein kinases (MAPKs) (p38, c-Jun N-terminal kinases 1, extracellular signal-regulated kinase 1/2), and their phosphorylated forms. Low-dose aspirin improved HFD-induced hyperinsulinemia and hyperlipidemia, recovered PT and aPTT, inhibited upregulation of adhesion molecules and chemokines and reduced expression of PKCα, IKKα, p65, and MAPKs. Low-dose aspirin ameliorates HFD-induced hyperlipidemia and hyperinsulinemia, and prevents HFD-induced expression of adhesion molecules and chemokine formation.

Objectives Previous studies have shown eugenosedin-A, a 5-HT1B/2A and α1/α2/β1-adrenergic blocker, is able to decrease cholesterol levels, hyperglycaemia and inflammation in hyperlipidaemic mice induced by high-fat diet (HFD). The aim of this study is to examine the effects of eugenosedin-A on the inhibition of adhesion molecules of platelets, the aorta and acyl-coenzymeA:cholesterol acyltransferase-1 (ACAT-1) of macrophages in a hyperlipidaemic rat model. Methods Six-week-old Sprague–Dawley rats were randomly divided into two control and treatment groups. The control rats received either a regular diet or HFD and the treatment groups were fed HFD with either 5 mg/kg eugenosedin-A or atorvastatin for a 10-week period. Key findings Compared with the two control groups, the HFD group had lower levels of high-density lipoprotein, higher concentrations of triglycerides, total cholesterol, low-density lipoprotein and insulin. The expression of adhesion molecules in platelets, aorta and monocyte-macrophage were enhanced by HFD. HFD also increased upstream proteins and their phosphorylated form in the aorta. In treatment groups, eugenosedin-A and atorvastatin improved HFD-induced hyperlipidaemia and levels of insulin. Eugenosedin-A reduced the upregulation of P-selectin, ICAM-1, ICAM-2, ICAM-3, VCAM, PECAM in platelets and inhibited E-selectin, ICAM-1, ICAM-2, ICAM-3, VCAM and PECAM protein levels in the aorta. Eugenosedin-A reduced the ACAT-1 protein expression of monocyte-macrophages. The expression of PKCα, MAPKs, IKKα and p65 and their phosphorylated form were reduced in treatment groups. Conclusions Taken together, hyperlipidaemia enhances the expression of adhesion molecules and ACAT-1 protein, and eugenosedin-A ameliorates those increases. Through inhibition of MAPK- and p-65-mediated NF-κB pathway, eugenosedin-A decreases the quantity of adhesion molecules.

Three isoeugenol-based eugenosedin chlorphenylpiperazine derivatives, Eu-A, Eu-B, and Eu-C, were synthesized and tested for their serotonergic, adrenergic antagonist, antioxidant, and anti-aggregation activities. In radioligand binding assays, all three agents displayed significant binding affinities on α1, α2, β1, 5-HT1B, and 5-HT2A receptors. In human platelet, they inhibited epinephrine and 5-HT-induced aggregation, and in human platelet with α2 and 5-HT2A receptors they had a competitive binding effect. Eu-B and Eu-C were more potent than Eu-A. All compounds had antioxidant effects derived from aryloxypropanolamine. Eu- A, Eu-B, or Eu-C (1, 3, 5 mg/kg iv) given to normotensive Wistar rats produced a dose-dependent decrease in mean arterial blood pressure and heart rate and when injected into the cisternum, Eu-A, Eu-B, or Eu-C (0.3, 0.03 µmol) increased blood pressure within 15 min. Pretreatment with any of the three agents inhibited clonidine (38 pmol)-induced hypotension. In vitro experiments, Eu-A, Eu-B, or Eu-C (1, 10, and 100 µM) competitively antagonized norepinephrine-, clonidine-, and 5-HT (10−8–10−4 M)-induced vasocontraction in isolated rat aorta, and competitively antagonized isoproterenol (10−8–10−4 M)-induced positive inotropic effects in a concentration-dependent manner in the isolated rat left atrium. In isolated rabbit ear arteries sensitized with 16 mM K+, all three agents antagonized 5-nonyloxytryptamine- and 5-HT-induced vasocontractions. These findings show that Eu-A, Eu-B, and Eu-C possess functional α1, α2, β1, 5-HT1B, and 5-HT2A receptor blocking activities. In conclusion, the changes in the position of chloride at phenylpiperazine influenced the serotonergic receptor, adrenoceptor antagonistic activities, but not anti-aggregation and antioxidant activities. Drug Dev Res 71:1–9, 2010. © 2010 Wiley-Liss, Inc.

Objectives Eugenosedin-A is a serotonin (5-hydroxytryptamine; 5-HT) 5-HT1b/2a and α1/α2/β1-adrenoceptor blocker with anti-oxidative, anti-inflammatory and free-radical scavenging activities. Previous reports demonstrated that 5-HT2a blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin-A and other agents in treating hyperlipidaemia. Methods C57BL/6J mice were randomly divided into seven groups, fed a regular diet or a high-fat diet alone or supplemented with one of five agents: eugenosedin-A, ketanserin, prazosin, propranolol or atorvastatin (5 mg/kg p.o.) for 8 weeks. Key findings Compared with the regular diet, the mice fed the high-fat diet had significantly higher body weight and glucose, insulin and lipid levels. Brain malondialdehyde concentration was increased and liver glutathione peroxidase activity decreased. Addition of eugenosedin-A to the high-fat diet resulted in less weight gain and reduced hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Lipid and glucose homeostasis were related to decreased hepatic lipogenesis mRNAs and proteins (sterol regulatory element binding protein 1a, fatty acid synthase, sterol-CoA desaturase) and restored adipose peroxisome proliferator-activated receptor γ expression. Eugenosedin-A also enhanced low-density lipoprotein receptor mRNA expression. Conclusions Eugenosedin-A may improve plasma lipid metabolism by increasing low-density lipoprotein receptor and peroxisome proliferator-activated receptor γ expression and diminishing sterol regulatory element binding protein 1a, fatty acid synthase and sterol-CoA desaturase. Reduction of plasma glucose and lipid levels may, in turn, reduce insulin concentration, which would explain the marked improvement in obesity-related hyperglycaemia and hyperlipidaemia. Furthermore, eugenosedin-A affected malondialdehyde concentration and glutathione peroxidase activity, suggesting it may have anti-peroxidation effects in mice fed a high-fat diet.

In this study, we investigate the protective effects of eugenosedin-A on p38 mitogen-activated protein kinase (MAPK), inflammatory nitric oxide (NO) and cyclooxygenase-2 (COX-2) pathways in a rat model of endotoxin shock. Rats were pretreated with eugenosedin-A, trazodone, yohimbine (1 mg kg−1, i.v.), aminoguanidine or ascorbic acid (15 mg kg−1, i.v.) 30 min before endotoxin challenge. Endotoxaemia was induced by a single i.v. injection of lipopolysaccharide (LPS, 10 mg kg−1). In rats not treated with eugenosedin-A, LPS increased plasma concentrations of NO and prostaglandin E2 (PGE2), and levels of p38 MAPK, inducible NO synthase (iNOS) and COX-2 proteins in the liver, lung, aorta and lymphocytes. In the pre-treated rats, eugenosedin-A not only inhibited the LPS-induced NO and PGE2 levels but also attenuated the LPS-induced increase in p38 MAPK and iNOS levels in the liver, aorta and lymphocytes. Eugenosedin-A also reduced LPS-induced COX-2 proteins in the aorta and lymphocytes. Likewise, aminoguanidine, ascorbic acid, yohimbine and trazodone were also found to decrease NO and PGE2 concentrations after endotoxin challenge. While aminoguanidine and ascorbic acid also attenuated the LPS-induced increase in p38 MAPK, iNOS and COX-2 proteins in the aorta and lymphocytes, trazodone and yohimbine inhibited only the increase in p38 MAPK, iNOS and COX-2 proteins in lymphocytes. Finally, eugenosedin-A (10−10-10−8 M) significantly inhibited the biphasic response induced by hydrogen peroxide (10−6-3 × 10−5 M) in rat denudated aorta. Taken together, the results of this study indicate that eugenosedin-A, as well as ascorbic acid, can attenuate free-radical-mediated aortic contraction and relaxation. It may therefore be able to reduce the damage caused by septic shock by inhibiting formation of p38 MAPK, iNOS, COX-2 and free radicals.

Pre-germinated brown rice (PGBR) can ameliorate hyperlipidemia, but the action mechanism is not clear. We focus the mechanisms of PGBR prevented hyperlipidemia. Six-week-old mice were divided into: standard-regular diet (SRD), high-fat diet (HFD) and HFD with PGBR (HFD + PGBR) groups for 16 weeks. The HFD group has higher concentrations of TG, TC, HDL and Non-HDL in the blood, and a higher atherosclerosis index (AI). The TG levels in the liver, and TG, bile acid levels in the feces were enhanced; and the total adipocytokines level in adipose tissue was reduced. The HFD group had higher protein expressions of SREBP-1, SCD-1, FAS, LDLR, and CYP7α1 in the liver. Moreover, the greater expressions of SREBP-1, SCD-1, FAS and the less expressions of PPAR-α and adiponectin were in adipose tissue. In the HFD + PGBR group, the PGBR regulated the levels of TG, TC, HDL, Non-HDL, AI and adipocytokines. PGBR increased more cholesterol and bile acid exhaust in feces. The SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7α1 and PPAR-α proteins in the liver; and the SREBP-1, SCD-1, FAS, PPAR-α and adiponectin proteins in adipose tissue were reversed by PGBR. Taken together, PGBR can improve lipid synthesis and metabolism, and we suggest PGBR is a recommendable food for controlling hyperlipidemia.

Consumption of medicinal mushrooms for disease prevention and maintaining health has a very long history in Asia. Grifola frondosa (Fr) S.F. Gray (GF) (Meripilaceae) is a medicinal fungus popularly used for enhancing immune systems, lowering blood glucose, and improving spleen, stomach, and nerve functions.This study examines the hypoglycemic effects of GF in vitro and in vivo, and analyzes the chemical profiles of its bioactive components.In vitro hypoglycemic effects of GF was evaluated enzymatically using α-amylase and α-glucosidase inhibition assays, whereas in vivo study was conducted on high-fat diet fed and streptozotocin (HFD + STZ)-induced hyperglycemic mice. GC-MS was used to determine the chemical profiles of bioactive components.The non-polar fraction of GF exhibited a stronger anti-α-glucosidase activity (IC50: 0.0332 mg/ml) than acarbose, but its anti-α-amylase activity (IC50: 0.671 mg/ml) was weaker. Oral administration of GF at 600 mg/kg (GF600) significantly lowered the blood glucose, HbA1c, average blood glucose, and serum total cholesterol levels in hyperglycemic mice. Although GF was found to contain mainly oleic acid and linoleic acid, their levels in the fungus were low, suggesting that the effects of GF on HFD + STZ-induced hyperglycemic mice could be due to factors other than these fatty acids.These results conclude that GF possesses anti-α-glucosidase activity, and hypoglycemic effect in HFD + STZ-induced hyperglycemic mice.

In this study the effects of low-dose aspirin (5 mg/kg) on adhesion molecule and chemokine expression in a hyperlipidemic rat model. Six-week-old Sprague-Dawley (SD) rats were assigned to two control groups receiving either a regular diet or high-fat diet (HFD) and a treatment group fed HFD with 5 mg/kg aspirin for a 10-week period. Compared with the regular diet control group, the HFD control group had higher body weight, lower levels of high-density lipoprotein, higher concentrations of insulin, triglyceride, total cholesterol, and low-density lipoprotein, but no differences in blood glucose and glycated hemoglobin. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) were clearly shortened in the HFD group. That group also had increased expression of intercellular adhesion molecule-1 (ICAM-1), ICAM-2, ICAM-3, vascular cell adhesion molecule (VCAM), platelet endothelial cell adhesion molecule (PECAM) and P-selectin in platelets and vascular adhesion protein-1 in lymphocyte and in aorta increased expressions of ICAM-1, ICAM-2, ICAM-3, VCAM, PECAM, E-selectin, monocyte chemoattractant protein-1 (MCP-1) and CCR2. The HFD rats also had increased PKCα, IκB kinase α (IKKα), p65, mitogen-activated protein kinases (MAPKs) (p38, c-Jun N-terminal kinases 1, extracellular signal-regulated kinase 1/2), and their phosphorylated forms. Low-dose aspirin improved HFD-induced hyperinsulinemia and hyperlipidemia, recovered PT and aPTT, inhibited upregulation of adhesion molecules and chemokines and reduced expression of PKCα, IKKα, p65, and MAPKs. Low-dose aspirin ameliorates HFD-induced hyperlipidemia and hyperinsulinemia, and prevents HFD-induced expression of adhesion molecules and chemokine formation.

Seven new sesquiterpenoids, lochmolins A–G (1–7), were isolated from a Taiwanese soft coral Sinularia lochmodes. The structures of these metabolites were elucidated by extensive spectroscopic study. Compounds 1–4 were found to inhibit the accumulation of the LPS-induced pro-inflammatory COX-2 protein in RAW264.7 macrophage cells.

Objectives Eugenosedin-A has been found to ameliorate high-fat diet (HFD)-induced hyperglycaemia and hyperlipidaemia in C57BL/6J mice. This study aimed to investigate the mechanisms of action of eugenosedin-A on endothelial function and inflammation in hyperlipidaemic mice. Methods C57BL/6J mice were randomly divided into two control groups and two treatment groups. The control mice received either a regular diet or HFD, and the treatment groups were fed HFD with either 5 mg/kg eugenosedin-A or atorvastatin for eight weeks. Key findings Mice fed a HFD had higher concentrations of nitrate (NO) but not prostaglandin E2 (PGE2), increased tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) mRNA and inducible nitric oxide synthase (iNOS) proteins, but decreased endothelial nitric oxide synthase (eNOS) proteins. HFD-induced upregulation of iNOS is associated with p38, extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK), PI3K and Akt/IKKα/p65. Eugenosedin-A and atorvastatin reduced HFD-induced TNF-α and IFN-γ mRNA, NO generation, upregulation of iNOS protein, and down-regulation of eNOS protein. Both agents inhibited p38, ERK, JNK and Akt/IKKα/p65 protein levels in the aorta. However, eugenosedin-A did not significantly reduce p38 in the liver. Conclusions Our results showed an association between obesity-induced inflammation and altered levels of TNF-α, IFN-γ, p38, ERK, JNK and Akt/IKKα/p65. Eugenosedin-A, like atorvastatin, could inhibit p38, ERK, JNK, Akt/IKKα/p65 proteins, as well as TNF-α and IFN-γ mRNA during the regulation of the obesity-induced inflammatory process.

Eugenosedin-B is able to block serotonin (5-HT) and alpha/beta receptors and to inhibit platelet aggregation. In Wistar rats, intravenous injections of eugenosedin-B (2.4, 7.2, 12 micromoL/kg) caused a dose-dependent decrease in blood pressure and heart rate. In contrast, intracisternal injection of eugenosedin-B (0.3, 0.03 micromoL) and an alpha2-antagonist yohimbine (0.03 micromoL) increased blood pressure and heart rate. Eugenosedin-B and yohimbine prevented hypotension induced by intracisternal injection of an alpha2-agonist clonidine (38 pmol). In in vitro experiments, eugenosedin-B (10, 10, 10 M) competitively antagonized norepinephrine-, clonidine-, and 5-HT (10 to 10 M)-induced vasocontractions in isolated rat aorta. It also competitively antagonized the isoproterenol (10 to 10 M)-induced positive inotropic effects in isolated rat atrium. These findings clearly suggest that eugenosedin-B possesses alpha1, alpha2, beta1, and 5-HT2A receptor blocking activities. In isolated rabbit ear artery sensitized with 16 mM K, eugenosedin-B antagonized 5-nonyloxytryptamine- and 5-HT-induced vasocontractions, indicating it also blocked 5-HT1B and 5-HT2A receptors. In radioligand-binding experiments, eugenosedin-B had significant binding affinities on alpha1, alpha2, beta1, 5-HT1B, and 5-HT2A receptors. In human platelets, eugenosedin-B inhibited epinephrine and 5-HT-induced aggregations. It also had competitive binding effects in human platelet with [H]yohimbine (alpha2), [H]ketanserin (5-HT2A). We conclude that hypotensive and vasorelaxant effects of eugenosedin-B can be attributed to its multiple actions on the blockade of 5-HT1B, 5-HT2A, alpha1/2 and beta1 receptors, and its ability to reduce platelet aggregation attributed to its blockade of alpha2 and 5-HT2A receptors.